~
`•
`atoo lea
`
`..,,--
`International Journal for Clinical and Investigative Dermatology
`
`181/1/90
`
`Comments
`
`Melagenina. An Analysis of Published and Other Available Data
`Nordlund, J.J.; Halder, R. (Cincinnati, Ohio/Washington, D.C.)
`. . . .. . .. .... . .. . .
`
`Clinical and Laboratory Investigations
`Idiopathic Recalcitrant Facial Flushing Syndrome
`Tur, E.; Ryatt, K.S.; Maibach, H.I. (San Francisco, Calif.)
`Malignant Melanoma at Sites of Therapeutic X-Irradiation
`McDonagh, A.J.G.; Wright, A.L. (Sheffield) . . ... . . . .
`Papillomavirus Common Antigen in Bowen's Disease
`
`. . .. .. . .... .. . . .. . . . . . . . .
`
`. . .. . .. . .. .. ..... . .
`
`18 9 0
`1 () nl ~~ Grussendorf-Concn, E.-I.; Giesen, M. (Aachen) . . . . . . . . .. . ..... . .. ... . . . . . . . . . ... .. . .
`.#
`£...
`/ ~~ ...
`.L t-~
`"
`
`/
`
`Granulocyte-Macrophage Colony-Stimulating Factor in Psoriasis
`Takematsu, H.; Tagami, H. (Sendai) .. . . . . .. . ... . .. .. . . . . . . . . . . . . . . . . ... . .. .. .. .
`Seasonal Modulation of Sebum Excretion
`--~--- Pierard-Franchimont, C.; Pitrard, G.E.; Kligman, A. (Liege/Philadelphia, Pa.)
`~~~~~;';;"~~'ta~Vapour Loss Threshold and Induction of Cholinergic Urticaria
`"r, R.A. ; Doegias, H.'M.G. (Groningen)
`.. . .. ... .. .
`. . . .. .
`
`.. .. . ... . . .. . . .. .
`
`. . . . . . . . . . • . .... . .. .
`
`r
`and Treatment
`() 1 '~ica Ke . onaz~le f~r Infantile ~ebo~rhoe~c Der~atitis .
`j U \.. t.l
`, Legralll, V., Palmier, c., Lejcan, S., SIX, M., Malevllle,J . (Bordeaux) .. . .. .. . ... . . ... .
`Tal b,
`Fuma c
`id Therapy in Psoriasis: A Double-Blind Comparison betw~en Fumaric Acid Compound
`er y and Monotherapy with Dimethylfumaric Acid Ester
`ie cr, c.; Hoop, D. dc; Langcndijk, P.N.J.; Loenen, A.C. van; Gubbels, J. (Amsterdam/Ede-Bennekom/Grave)
`:~FIl[fg;rBlanching after Epicutaneous Application of EM LA Cream. A Double-Blind Randomized Study
`among 50 Healthy Volunteers
`Villada, G.; Zetlaoui, J.; Revuz, J. (CreteH) .. . ... •. . .. . . . . . . . .. .•.. . .. . •. . ....• .
`
`5
`
`8
`
`11
`
`16
`
`21
`
`23
`
`26
`
`33
`
`38
`
`41
`
`44
`
`48
`
`51
`
`54
`
`56
`
`Case Reports
`Urticaria with Macroglobulinaemia. Disease Activity Associate Alterations in Immunoglobulins Profile
`and Bone Marrow Hypodiploidy
`Bonnetblanc, J.M. ; Drouet, M.; Laplaud, P.; Bedane, c.; Bernard, P. (Limoges) . .. . ... . . . .. . .. ... .
`Intractable Epidermolysis bullosa acquisita: Efficacy ofCiclosporin A
`Merle, c.; Blanc, D.; ZuItak, M.; Landuyt, H. van; Drobacheff, c.; Laurent, R. (Besan~on) .. . .... . . . .. .
`Familial Pemphigus vulgaris
`Katzenelson (Weissman), Y.; David, M.; Zamir, R.; MeJlibovsky, J.; Idises, c.; Sandbank, M. (Pctah Tiqva/
`Tel Aviv)
`... .... . . . ... . . .. . .. . ..... . . . ..... ... .... .. .. . . . . .. ... .. .
`Psoriasis Related to Angiotensin-Converting Enzyme Inhibitors
`Wolf, R.; Tamir, A.; Brenner, S. (Tel Aviv)
`.. .. ... . . . ..... ... . . ... . .. . . .. .. . .. . ... .
`Subcutaneous Fat Necrosis with Thrombocytopenia in a Newborn Infant
`Wolach, B.; Raas-Rothschild, A.; Vogel, R.; Choc, L.; Metzker, A. (Kfar Saba/Petah Tiqva/Tel Aviv)
`Leg Ulcers in a Patient with Spherocytosis: A Clinicopathological Report
`Vanscheidt, W.; Leder, 0.; Vanscheidt, E.; Wokalek, H. ; Wilmer, J.; Hofmann, E.; Schopf, E. (Freiburg i.Br.) . . .
`
`. . .. .. .
`
`KAR.GER.
`
`(Continued on back cover)
`
`S. Karger
`Medical and Scientific
`Publishers
`Basel · Munchen
`Paris· London
`New York . New Delhi
`Bangkok· Singapore
`Tokyo· Sydney
`
`Sawai (IPR2019-00789), Ex. 1017, p. 001
`
`

`

`Derm atologica 1990;18 1 :33- 37
`
`© 1<)<)0 Karge r AG. Basel
`OO II - <)0751<)OIlRI I--D033 $2.75/0
`
`Fumaric Acid Therapy in Psoriasis: A Double-Blind
`Comparison between Fumaric Acid Compound Therapy and
`Monotherapy with Dimethylfumaric Acid Esterl
`, A. C. van Loenen", 1. Gubbels d
`C. Nieboer a, D. de HOOpb, P. N.J. LangendijkC
`"Depa rtm e nt of De rmato logy, Free Uni versity Hospital , Amsterd am; bGelderse Va llei Hospital , Ede-Bennekom; ' Department of
`Pharmacy , Free Unive rsity Hospital, A msterda m , a nd "Organizatio n fo r Resea rch and Management , G rave , The Netherl ands
`
`Key Words. Psoriasis· Oimethylfumaric acid ester' Monoethylfumaric acid ester· Fumaric acid therapy
`
`Abstract. In a 4- month double-blind study the effects of dim ethylfumaric acid esters (DMFAE-EC) and DMFAE
`plus salts of monoethylfum aric acid esters (fum aric acid combination, FAC-EC) in enteric-coated tablets were com(cid:173)
`pared in 22 respectively 23 patients with psoriasis. In both groups about 50% showed a co nsiderable improvement , i.e.
`the initial score was more than halved. The therapeutic effects showed no significant differences in both groups with
`respect to the total psoriasis score or the different parameters. In the FAC-EC group the effects were obtained mo re
`rapid ly. Most frequently observed side effects in both groups were flushings, stomachache and diarrhea . Due to these
`co mpl ai nts 3 respectively 8 patie nts discontinued therapy. Eosinophilia , leukopenia and lymphopenia were the most
`freq uently observed differe nces in lab tests. It was concluded that FAC-EC had no significantly better effect than
`monotherapy with OMFAE-EC. Moreover, enteric coating of the tablets did not prevent stomach complaints. Until
`more information has been obtained about the pharmacokinetics, the toxicity and optimal composition of the drug , the
`fumaric acid therapy in pso riasis should be seen as experimental.
`
`The fumaric acid (FA) the rapy is a new syste mic medi (cid:173)
`cation with FA derivatives that has gai ned an increasing
`popularity amo ng psoriasis patients in several countries in
`western E urope .
`Several doubl e-blind studies have indeed shown that
`dimeth ylfumaric acid ester (OMFAE) and salts from
`mo noet hylfumaric acid
`(MEFAE) combined with
`DMFAE [2] have a positive therapeutic effect on pso(cid:173)
`riasis [t , 2]. The same studies showed that OMFAE was
`clea rly more effective than the Na salt of MEFAE, which
`only produced some effect when given in higher dosages
`[1].
`The mechanism of the effects of these substances is
`unknown . The view, originally held by Schweckendiek
`[3], was that these substa nces influenced the citric acid
`
`Suppo rted by a grant from the Stichting GelO ndh eidslOrg-onder(cid:173)
`lOek Ijsselmo nd , Zwolle, The Ne the rl ands.
`
`cycle . This could not be confirm ed by us in a number of
`unpublished experiments with both isolated mitochondria
`and hepatocytes . It is a known fact, however, that
`MEFAE and OMFAE [unpubl. observatio n] inhibit the
`mitosis of PHA-stimulated lymphocytes [4] and epithelial
`cell lines [5] . Little is known about the pharmacokinetics
`of the FA derivatives.
`Both DMFAE and MEFAE salts form the active
`ingredients of enteric coated (EC) tablets that are usually
`prescribed in FA therapy . This combination seemed to be
`based on historical factors rather than a ratio nal ther(cid:173)
`apeutic approach. The question arose whether this com(cid:173)
`bination was not too complicated and monoth erapy was
`just as effective. T he aim of our study was therefore to
`assess the therapeutic efficiency of DMFAE monother(cid:173)
`apy compared to that of DMFAE combined with
`MEFAE salts using the same DMFAE dosage and dosage
`form (EC tablets) .
`
`Sawai (IPR2019-00789), Ex. 1017, p. 002
`
`

`

`34
`
`Nie boL! r/dc Hoop/ Lan gc ndijk/v<l n LOL! nc n/Gubbe ls
`
`Table I. Co mparati vcs rud yon th ceffectsofDMFAE-EC(n = 22)
`a nd FAC-EC (n = 23) o n 45 psoriasis patie nts
`
`Medication
`
`n
`
`Improve me nt
`
`Dete r(cid:173)
`io rat io n
`
`Disco n(cid:173)
`tinu at ion
`
`< 25% 25-50% > 50%
`
`DMFA E-EC 22
`FAC-EC
`23
`
`5(22) 3 ( 14)
`1 (4) 2 (9)
`
`10 (45)
`12 (52)
`
`o
`o
`
`4( 18)1
`8 (35)"
`
`Figures in pa re nthescs a rc pe rcc nt ages .
`Do 'agc DMFAE-EC: 120-480 mg/day.
`Dosagc FAC-EC: 1-4tablc ts/d ay .
`A ll discontinued beca usc o f side e ffec ts.
`Discon tinucd beca usc of side effects, I for othe r reasons .
`
`Material and Methods
`
`Medicotiol/
`T he two diffe re nt drugs for thi s study wc rc suppli ed in EC tab lc ts
`whi ch we re i ndistinguishab lc in sizc , fo rm a nd color . The mo noth e rapy
`tah le ts (DMFAE-EC) co nta in ed DMFA E , 120 mg pc r tab lc t. T he
`co m hi na ti o n the rapy tab le ts (FAC-EC) co nta in cd a n equivalent
`a mo unt o f 120 mg DMFA and an additi o nal a mo unt of 5 mg ma gnc(cid:173)
`sium-MEFA,3 mg zin c-MErA and 87 mg calcium -M EFA. Th e la tt l! r
`co mbin a ti o n is used mos t frcque nt ly in FA th c rapy. Th c two batchcs uf
`DMrA E-EC and FAC-EC wc rc produccd by the Kc the l Pharmacy ,
`Schi cdam , Th e Net he rlands. Q ua lit y co ntrol o n bo th batchcs was d o nL!
`at th e pha rm acy labo rato ry, Free U ni vcrs it y, A mstc rd a m , The Ne thc r(cid:173)
`lands. T hc qu ality co ntrol co nsistcd o f idc ntification (o n DMFAE fo r
`DMFA-EC and DMFA E , MEFAE , magnesi um , zin c a nd calciu m for
`FAC-EC) . qualltitati o n o f co llte nt s (hetwee n 95 a nd 105% o f th e
`declared amount) by hi gh-pe rforma nce
`liquid chro ma togra )h
`(DMFA E co nte nt for DMFAE-EC a nd DMFAE - ,lI1d total MEFIA~
`co nte nt for FA C-EC) and co ntro l o n e nte ric coatin g acco rdin g to th e
`US P XX I 101. Bot h ba tchcs passL!d thc tes ts in t he quality co nt ro l.
`
`PI/tiel/ts
`Beforc e llt e ring the study patie nt s we re in for med ve rball y and gavc
`tlu; ir co nsc nt. Random ization int o two g ro ups was made bctwccn 45
`patic nts , 25 fe mal c , 20 ma lc, aged hc twec n 18 and 70 years: 22 we re
`t rcatcd with DMFAE-EC , 23 with rAC-Ec. At the c nd ofthcstudy:l:l
`pa ti c ntsco uld becva luatcd , 18 had bcc n trcated with DMFA E-EC a nd
`15 with FAC-EC. At Icas t 10'1.. of the body surface was affected. A t th e
`beginnin g o f th e stud y 22 o f th cSL! 33 pati e nt s showcd th e plaqu l! type,
`10 th e macu lar typc and I th c g uttat e type o f pso ria sis . II patie nts had
`joint co mplaint s , 6 in th c DMFA E-E g ro up and :) in th c FA C-EC
`gJ"LlUp. Th l! stud y was pc rfo rm cd undc r a protoco l app roved by th e hos(cid:173)
`pita l's E th ical Co mmittcl!.
`
`Dosl/ge
`T he starting dosage wa s I tabl e t a day . Thi s was increased wec kl y
`up to a max imum of 4 tablet s a d ay ha nd ed out in 2 ad mini stra tion s. 6
`patic nts o fth e DMFAE-ECgroup and4 pati e nts o fth e FA C-EC gro up
`did not tolerate thi s dosagc . T hey we re trea ted with I tablc t twice a da y.
`
`Eva/uatioll
`A sim plifi ed 'pso ri asis a re a a nd seve rit y score' was appli cd , in
`whi ch 5 para me te rs wc re eva luatL!d : Exte nt: 0 = c ntirdy cl ea n,
`../ = 35-
`1=< 10% hod y surface affectc d. 2 = 10- 25%. :l=25-35°!t"
`SO% , 5 => 50% bo dy surfacc affeClL!d : sca lin g : O= no ne , l = sli ght ,
`2 = mod e rate, 3 = scve re, spo ntan eo us; t hi ck ness o f pa tehes: 0 = 110
`infiltrati o n, I = sli ght infil tration , 2 = appa rc nt infi ltra ti o n , nol ra iscd,
`3 = ra iscd; rcd ness: O= no ne , I = pin k . 2 = brig ht rcd , 3 = fi c ry red or
`red-purple ; itching: 0 = non c , I = slight . 2 = mo dc ratc , 3 = st ro ng. The
`max illlumtotal score was 17 . thL! minimum O. ThL! paticnts werc exa m(cid:173)
`in ed cve ry 4 wec ks a nd th c psoriasis sco re as wc ll as th e sidc c ffects
`WL!rc rcg istl!red .
`Apa rt from thi s scm L! a gc nL! ral eva lu ation was g ive n at till! c nd o f
`thc cx aminat io n by thc invest iga tor and the pa ti e nt (d c te ri oratcd , no
`cha nge , sli ght improvc me nt . strong imp rovc mL! nt , full clea ra ncL!). The
`effcct o n join t complaillls was judged o n t hL! basis o f thc impress io ns of
`th L! pati e nts: de te ri o ra ted , un c ha nged ,
`imp roved , co nsidc ra bl y
`im proved.
`Dur ing cach visit thc fo ll ow ing laho ratory tes ts werc carried out:
`blood : pe riph e ra l Ic ukocytcs plus diffc rc ntia l co unt : serulll : BU N,
`alka li ne phos phmasc , LD H , ALAT, ASAT, y-GT: u rinc: prote in and
`scdim c nt.
`T hc study was ca rri ed o ut in the mo nth s fr o lll Ocrobc r to A pril , rhe
`duratio n of thc st ud y was 4 mo nth s pc r pati e nt. Statisti ca l analysis was
`ca rri L!d o ut using Fische r's exact tes t a nd th c X1 test.
`
`Results and Side Effects
`
`T he individual res ults a re shown in table 1. Compared
`to the initial population sco re, a co nside rable improve(cid:173)
`me nt (i. e . score more tha n halved) was obse rved in 45 %
`of the patie nts treated with DM FAE-EC and in 52% of
`the trea ted with FAC-EC. This improveme nt was stat is(cid:173)
`ti ca ll y significant.
`I n both gro ups 4 patie nts ( 18 and 15%) showed a full
`clea rance . Co nside rable improveme nt occurred in 15 o ut
`01'22 (68%) patie nts with th e plaque type a nd in 40 ut of 10
`(40%) of those with the macul ar type. The patient with
`the guttate type showed a full clea ra nce afte r a treatm e nt
`of 2 months wit h FAC-EC, but had a n ex te nsive relapse 1
`mo nth late r eve n th ough the th erapy had bee n continued.
`For 5 patie nts (22% ) in th e DMFA E-EC group a nd 1
`patie nt (4% ) in th e FAC-EC gro up the psoriasis did not
`show a ny reaction to the thera py. T he observed differ(cid:173)
`ences betwee n the two gro ups appea red to be not signifi(cid:173)
`ca nt. Dete rioration , th at is a n increase of the score up to
`more tha n 125% , was no t obse rved in e ithe r of the
`groups.
`T he course of the score in both groups with rega rd to
`the total ave rage score a nd the se pa rate parame te rs is
`shown in fi gure l a, b. It covers the observat io ns of those
`pat ie nts who could be evaluated afte r 4 months: 18 in the
`DMFAE-EC gro up and 15 in the FAC-EC group . The
`
`Sawai (IPR2019-00789), Ex. 1017, p. 003
`
`

`

`Fumaric Acid The rapy in Psori asis
`
`35
`
`15
`
`o
`lfl
`
`• = DMFA -EC
`A = FAC- EC
`
`Fig. 1. Course of the total psoriasis score andoft he5 parameters in
`patients treated with DMFAE- EC (n = 18) or FAC-EC (n = 15) during
`4 months. a Tota l psoriasis severity score. b Perce nt decrease of the 5
`parameters of the severity score.
`
`'iil
`;Q 5 - ' - - - , , - - - - , - - - - - , - - _ , -_ _ - , _ a
`v
`III
`IV
`Time (28 days) I.
`
`% Extent of' eruption
`100
`
`Induration
`
`Scaling
`
`Redness
`
`Itching
`
`50
`
`III
`
`IV
`
`V
`
`III
`
`IV
`
`V
`
`III
`
`IV
`
`V
`
`III
`
`IV
`
`V
`
`4-- , ---,- - , - - , - h
`III
`IV
`V
`
`Time (Ze days) 4
`
`tota l average sco re in the DMFAE-EC group dropped
`from 9.7 to 4.1 and in the FAC-EC group from 10.5 to 4.1.
`The course of this score in both treatment groups was not
`significa ntly different at any time point (I-V). Subse(cid:173)
`quently the separate parameters too did not show a sig(cid:173)
`nificant difference in time course. The results after 4
`mo nths were not statistically different.
`The jo int compl aints of the 6 patie nts in the DMFAE(cid:173)
`EC group showed considerable improvement for 2
`patients, and some for 1, and deteriorated or remained
`unchanged for the other 3. In th e 5 patients in the FAC(cid:173)
`EC gro up a considerable improvement occurred in 2 cases
`and a slight improvement in 3 cases.
`T he ge neral evaluation of the therapy by the patients
`usually corresponded with that of the investigators.
`T he subjective and objective side effects are shown in
`tab le 2. The flushings sta rted 3-4 h after the tablets were
`taken. They invo lved a feeling of tingling heat, accompa(cid:173)
`nied by diffuse redness, which continued for about half an
`
`hour mainly localized in the face, anns and the upper part
`of the body . This symptom was not constantly present and
`in the course of the treatment its frequency decreased.
`One patient was troubled by this sy mptom to such an
`extent that he discontinued the treatment . The gastroin(cid:173)
`testinal complaints, on the other hand , presented a real
`problem. More than half the patients were troubled by
`serious stomach complaints, invo lving gastralgia, but also
`nausea, vomiting and diarrhea. For 14% (n =3) of the
`patients in the DMFAE-ECgroup and 30% (n = 7) in the
`FAC-EC gro up these complaints were a reason to discon(cid:173)
`tinue the therapy. Another patient had to discontinue th e
`DMFA E-EC therapy beca use his tablets had been stolen.
`The abnormalities which were registered in the blood
`most generally were: leukopenia «3.0 X 109/1) , lympho(cid:173)
`penia « 15%) and eosinophilia (> 5%) . The former two
`developed in the course of the 3rd and 4th months. The
`eosinophilia usually began in the first 2 months and disap(cid:173)
`peared spontaneously in most of the cases.
`
`Sawai (IPR2019-00789), Ex. 1017, p. 004
`
`

`

`36
`
`Nie boe r/de Hoop/Lange ndij k/van Loe ne n/G ubbels
`
`TlIble 2. Side e ffects during tre atme nt of psori asis wit h DMFAE
`(n = 22) o r FAC -EC (n = 23) ove r a pe ri od of 4 mo nths
`
`DMFAE-EC
`
`FAC-EC
`
`(n =22)
`
`n
`
`o
`
`3
`3
`8
`
`o
`1
`o
`
`%
`
`86
`55
`50
`9
`5
`5
`
`o
`
`14
`12
`35
`
`o
`5
`o
`
`(n = 23)
`
`n
`
`%
`
`20 1
`143
`l43
`1
`0
`
`2
`
`3
`2
`3
`
`0
`0
`
`87
`6 l
`6 l
`4
`0
`4
`
`9
`
`13
`8
`13
`
`0
`0
`4
`
`Sy mpto ms
`Flushing
`Diarrhea
`Nausea/stomache
`Ge ne ral ma laise
`Dizziness
`H eadach e
`La boratory
`Urine
`Albuminuria
`Blooel
`Le ukope ni a
`Lymphope nia
`Eos ino phili a
`I ncrease o f
`C reatinine/urea
`A lkaline phosphatase
`ASAT/ALAT
`
`I Patient discontinue d the treatm e nt as a result o f thi s symptom .
`3 Patie nts disco ntinu ed th e trea tm e nt as a res ult of these symptoms .
`7 Patie nts d iscontinue d th e tre atme nt as a result of these symptoms .
`
`DisclIssion
`
`In this study th e treatment of psoriasis with FA esters
`led to evident improve ment in about 50% in the pati e nts .
`This percentage was even highe r when one did not consid(cid:173)
`e r the initial study population, but only those patients who
`could be evaluated after 4 months. In that calculation the
`improvement percentage (i. e. a psoriasis seve rity sco re
`morc th a n halved) was 55% in the DMFAE-EC group
`and 80% in the FAC-EC group . The course of the total
`score and of the separate parameters during the 4 months
`of the study showed a te ndency towards a more rapid
`res ult with FAC-EC than with DMFAE-EC monother(cid:173)
`apy. Howeve r, this diffcrence was not significant and the
`final score in both groups was the sa me .
`Of th e side effects the freque ntly occurring gastroin(cid:173)
`testinal sy mptoms should be mentioned first. Fairly often
`the diarrhea , frequ e ntly accompa nied by stomachaches,
`form ed th e main reason to discontinue the therapy . In a
`numbe r of cases these side effects disappeared sponta-
`
`neously in due course, for other patie nts loperamide
`resolved this complaint. Some patie nts had predom(cid:173)
`inantly serious gastric complai nts, despite the use of Ee
`tablets. In a numbc r of cases Antage l (Solutio Antacida ,
`Dutch Pharmacist Formulary) could preve nt stomach
`complaints. Another way to preve nt these complaints is
`lowering of the starting dosage to 30 or 60 mg D MFA with
`subsequent weekly increases. The gastric complaints
`must be taken seriously as we obse rved aggravation of
`ulcera ventricu li and eve n once a perforation of th e stom(cid:173)
`ach during treatme nt with noncoated capsules with
`DMFA E.
`The experience of th e f1u shings was less serious , flush(cid:173)
`ing did not occur each time the drug was take n and it often
`decreased in the course of the study. Genera l malaise
`(without complaints of the digestive tract) was experi(cid:173)
`enced by several patie nts, but was take n for granted
`.
`because of the positive the rape utic results .
`The most striking differe nces in lab tests were thos.e 111
`the blood count: le ukope nia , lymphopenia and eoslOO
`-
`philia . The latter mainly occurred in the first 2 months and
`usually disappeared sponta neously . [t did not inv~lve
`allergic symptoms, neith e r of the skin nor of the respIra(cid:173)
`tory tract. The leukope nia was in most cases the result of a
`considerable decrease of the lymphocytes. It is a well
`known fact that MEF AE inhibits the prolife ration of
`PHA-stimulated lymphocytes among other things. We
`noticed that DMF AE had the sa me effect. It was re mark(cid:173)
`able that th e lymphopenia in this study occurred far less
`freque ntly than in an earlie r study , in which more tha~)
`50% of the patients showed this phenome non [1]. In thiS
`ea rlier study , instead of the EC tablets, capsules fill ed
`with a coated granulate were used , which already re leased
`DMFA E in the stomach. It was demonstrated there that
`the lymphopenia was caused by a selective decrease of T
`suppressor (Ts) lymphocytes a nd , less ex plicitly , of the I~
`lymphocytes, whereas the number of T he lper ce s
`re mained constant. An explanation for these phe nomena
`could be that the Ts and B lymphocytes are a popl~l~t~on
`of cells with a rapid proliferation of which the cell diVISion
`is inhibited by relatively high serum levels of DMF~E
`after prompt resorption due to prepyloric re lease . So far
`th e lymphopenia has disappea red in all patie nts in the
`course of 2-4 months after discontinuation of the th e rapy .
`In 2 patie nts of the FAC-EC group, albuminuria
`occurred which was not accompanied by a rise of the
`serum creatinine and urea. One should , howe ver , not rule
`out the possibility of serious nephrotoxicity. Acute tubu(cid:173)
`lus necrosis has bee n re ported in 4 patients and could very
`probably be ascribed to FA th e rapy [7J .
`
`Sawai (IPR2019-00789), Ex. 1017, p. 005
`
`

`

`Fum aric Acid T he ra py in Pso ri as is
`
`37
`
`In summ a ry o ne could state that treatme nt of pso riasis
`with FAC-EC does not res ult in a bette r the rape utic res ult
`compared to DM FAE-EC monotherapy. EC of the
`tablets does not preve nt the freque nt occurre nce of gas(cid:173)
`tric complaints. rn the light of a numbe r of serio us and rel(cid:173)
`atively freque ntly occurring side effects th e FA the rapy is
`to be seen as expe rim e ntal until the re is more inform atio n
`abo ut th e pha rm aco kinetics, toxicity a nd optim al compo(cid:173)
`sition of the drug.
`
`References
`
`4 Pe tres J , Ka lho ff BW, Ki efe r G , et a l: Ocr Ei nfiuss vo n Fum arsii ure
`Mo noa th yleste r a uf di e Nuci einsa ure unci Prote insy nthese PH A
`stimuli e rte r me nschli che r Lymp hocyte n. Arch Dermatol Res 1975:
`254:67-73.
`5 SchroeffJ G van de r , O udh orn C , Nligte re n-HlI ying WM , Ponec M:
`Inhibi to ry effects of fumari c acid derivatives o n cell pro li feratio n
`a ncl diffe re ntiation. J In vest D erm atol 1989;92 :537 A .
`6 United Stat es Pharmacope ia , ed 2 1. Monograp hs 711 a nd 725.
`Rockville , U ni ted States Pha nn acope ial Conve nti o n , 1984 , pp
`1243- 1244 , 1245-1246.
`7 Rood nat, 11 , C hristi aa ns MHL, Nugte re n-Huying W M , SchrodT
`JG van der , Zo uwe n P va n der , Stri cke r BH C , Wee ning JJ , C ha ng
`PC: Ak ute Ni e re ninsuffizie nz bei de r Be handlung der Pso ri as is mit
`Flim arsU ure-Es te rn . Schwe iz Mcd Woche nschr 1989 ; 11 9: 826- 830 .
`
`N ieboe r C, I-loop 0 de, Loc ne n A C va n , La nge ndij k PNJ , Dij k E
`va n: Syste mi c thcrapy w ith fum a ri c acid der ivativcs : New possibili(cid:173)
`ti es in the tre a tm e nt o f pso ri asi s. J A m Acad De rm atol 1989;
`20:601 - 608 .
`2 Nugte re n- Hu ying W M , Schroeff JG va n cle r: Fum aa rzu uthe ra pi e
`voor pso ri as is. 235 th Ge n Mee t D utch Ve re ni ging De rm a tol Ve ne(cid:173)
`reo l, Le iden , 1989 , pp 6 1-62 .
`3 Schwee ke ndi e k W : D ie Psoriasis vul gari s. e ine stolTwechselbe(cid:173)
`d ingte H a ut kra nkhe it. Erfa hrungs he il k unde 1984;33 :850- 858.
`
`Received : A ugust 4 , 1989
`Accepted : Nove mbe r 17 , 1989
`
`Dr. C. Nie boe r
`De partm c nt of D e rma tology
`Aca de mi c Hospital Free Uni ve rsity
`De Boele laa n 111 7
`N L- 108 l A mste rda m , HV (The Ne the rl a nds)
`
`Sawai (IPR2019-00789), Ex. 1017, p. 006
`
`